Our previous work showed that down-regulation of a critical IAP molecule using RNA interference techniques is capable of overcoming an important barrier to cancer cell death in intrinsically apoptosis-resistant human lung cancer cells. We have also performed preclinical work investigating several members of a novel drug class which inhibits the same IAP molecule pharmacologically and determined its efficacy in lung cancer cells. Our results appeared to show that all members tested from this new pharmacologic drug class are as effective as RNA interference techniques, however some limitations exist. In select lung cancer cell lines, cell death can not be achieved and thus resistance to this drug class exists. In contrast, in the majority of lung cancer cells, these small molecule drugs can exert similar effects of reversing cell-death (apoptosis) resistance, rendering these cancer cells renewed-susceptibility to apoptosis induction and resulting in cancer cell death. Our continuing work is focused on completing the necessary preclinical work to translate this drug class into the clinical setting and delineating the mechanism(s) for drug resistance of this small molecule mimic in lung cancer, as this would hold direct implications as to the appropriate patients who should and should not receive this drug in a clinical trial. In this first goal, we are taking three approaches: 1) to bring this new drug class directly into clinical trials upon completion of preclinical studies, provided the availability of the drug for use in the NIH Clinical Center; and 2) to investigate the effectiveness of using nanoparticle delivery of our (already effective in-vitro and in vivo) RNAi modulation of the apoptosis pathway. In approach #1, we are progressing to in-vivo evaluation in small animal models using the novel combination of this small molecule mimic and an upstream apoptosis inducer although this has been hampered by pharma-related issues. In approach #2, we have performed in-vitro and in vivo testing of a nanodelivery platform we designed and fabricated for anti-cancer therapy to determine the critical modifications necessary to produce a viable clinically useful nanodelivery vehicle. In this second approach, we have made significant advancement and have discovered a method to markedly augment preferential nanoparticle uptake by cancer cells. As proof of principle, we have evaluated this engineered nanoparticle platform and used it to deliver anti-cancer pro-apopotic siRNAs via systemic adminstration and resulting in signficant tumor growth arrest in vivo. Additional delivery payloads have been trialed with our nanoparticle platform, with similar success in producing bona fide cancer cell entry of large numbers of nanoparticles. To our knowledge, this is the first report of an engineered nanoparticle which is capable of engaging the cancer cell's internal mechanisms of cellular uptake and upregulating it to increase nanoparticle uptake in a self-compounding manner. This work has been published in the high-impact journal Biomaterials now (Tobin et al. Biomaterials 2013) and served as the basis for a US and international patent filed by the NIH.